First-in-Human, Double-Blind, Randomized Controlled Trial of an Oral Dose of GnRH Antagonist TU2670 in Healthy Women

Abstract

Objective: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TU2670, a novel orally active, nonpeptide gonadotropin-releasing hormone (GnRH) antagonist administered to healthy female participants.

Methods: This was a first-in-human, multicenter, phase 1, randomized, double-blind, placebo-controlled, single-dose ascending trial that took place in multiple medical centers. A total of 16 healthy premenopausal women (23 to 45 years of age) were randomized and received 20, 40, 80, and 160 mg TU2670 (GnRH antagonist) or placebo 7 days (+/- 1 day) after the onset of menstrual bleeding. We performed a noncompartmental analysis for pharmacokinetic parameters and calculated relative minimum concentration values (C-min, % Baseline) of serum pharmacodynamic (PD) markers (luteinizing hormone [LH], follicle-stimulating hormone [FSH], and estradiol).

Results: There were no significant differences among treatments with respect to vital signs, electrocardiography, adverse events, ovulation test results, and ultrasonography. The median T-max of TU2670 occurred 0.75 to 1.00 hours after dosing, and concentrations then declined, with a mean apparent half-life (t(1/2)) of 3.0 to 5.9 hours. AUC(last) (17.7-417.9 ng.h/mL) and C-max (8.1-95.4 ng/mL) increased in a dose-dependent manner. The PD analysis after a single administration of TU2670 revealed dose-dependent suppression of LH, FSH, and estradiol. Maximal suppression of the pre-dose baseline (%) was 58% to 82% at 6 to 8 hours for LH, 28% to 39% at 6 to 12 hours for FSH, and 34% to 82% at 12 to 24 hours for estradiol.

Conclusion: The single administration of TU2670 in healthy premenopausal women was well tolerated and resulted in the dose-dependent suppression of LH, FSH, and estradiol, suggesting rapid and significant inhibition of pituitary and ovarian hormones.